Iron-Catalyzed Ortho C–H Methylation of Aromatics Bearing a Simple Carbonyl Group with Methylaluminum and Tridentate Phosphine Ligand

Abstract

Iron-catalyzed C-H functionalization of aromatics has attracted widespread attention from chemists in recent years, while the requirement of an elaborate directing group on the substrate has so far hampered the use of simple aromatic carbonyl compounds such as benzoic acid and ketones, much reducing its synthetic utility. We describe here a combination of a mildly reactive methylaluminum reagent and a new tridentate phosphine ligand for metal catalysis, 4-(bis(2-(diphenylphosphanyl)phenyl)phosphanyl)-N,N-dimethylaniline (Me2N-TP), that allows us to convert an ortho C-H bond to a C-CH3 bond in aromatics and heteroaromatics bearing simple carbonyl groups under mild oxidative conditions. The reaction is powerful enough to methylate all four ortho C-H bonds in benzophenone. The reaction tolerates a variety of functional groups, such as boronic ester, halide, sulfide, heterocycles, and enolizable ketones.

Iron catalyzed methylation and ethylation of vinyl arenes

“…27–33 Li and co-workers 29 developed a procedure for the methylation of aryl C–H bonds using dicumyl peroxide as the methylation reagent, and DiRocco and co-workers developed a procedure for the late-stage methylation of heterocycles with peresters as methyl sources. 31 Both examples mentioned above worked on the methylation of arenes or heterocycles, 34,35 rather than double bonds.…”

Regioselective C−H Alkylation via Carboxylate‐Directed Hydroarylation in Water

“…Hitherto, ortho ‐alkylations of benzoic acids remain rare, and alkyl sources are so far limited to dihalogenoalkanes, epoxides, alkyl trifluoroborates, or trimethylaluminium . Considering that olefins are generally cheaper and more readily available than other alkylating agents, the alkylation of benzoic acids with olefins attracts increasing attention.…”

A Tandem Enzymatic sp2‐C‐Methylation Process: Coupling in Situ S‐Adenosyl‐l‐Methionine Formation with Methyl Transfer

“…Regiospecific, late‐stage methylation is a powerful strategy for tuning the physical and biological properties of small molecules and bio‐macromolecules . At present, synthetic methodologies that methylate C(sp 2 )−H bonds are predominantly limited to transition‐metal‐catalysed strategies, which require elevated temperatures and the need for additives such as ligands and oxidants . In addition, these methodologies are typically regioselective rather than regiospecific, thus further restricting their scope .…”